The overall goal of this comprehensive Program Project is to establish a conceptual framework of the molecular and cellular mechanisms that control cholesterol absorption and transport, with the primary focus on luminal events leading to cholesterol uptake by the intestine. A multi- disciplinary approach will be used to interrelate mechanistically the role of dietary and genetic factors in cholesterol absorption is dependent on luminal lipid composition and on the level of expression of proteins involved in lipid digestion and transport. This hypothesis will be tested in 3 independent projects: one clinical study of cholesterol absorption in humans will interface with two basic research projects utilizing animal models to investigate regulatory mechanisms of cholesterol absorption. Thus, observations made animals in animals models can be examine din human subjects to determine clinical relevance, and the results of humans studies can be studied for mechanistic details in animals. Project 1 will test the hypothesis that alteration of intraluminal bile acid and lipid composition will impact cholesterol absorption, which in turn will impact on plasma and LDL cholesterol levels in humans. Project 2 will examine the role of bile salts in cholesterol solubilization, cholesterol incorporation into micelles and vesicles, and its subsequent delivery to the enterocytes. Project 3 will test the hypothesis that the level of lipolytic enzymes secreted by the pancreas, together with the bile salts and lipid constituents in the lumen, mediate cholesterol absorption efficiency by altering the physicochemical properties of the lipid substrates. These research projects will be supported by facilities in the Administrative Core, Animal Physiology and Lipid Analysis Core, Immunology and Molecular Biology Core, and Biostatistics Core. Because high dietary cholesterol intake is a major risk factor for heart disease, diabetes, obesity, and certain forms of cancer, results of this Program will provide necessary information for ration design of dietary and/or therapeutic treatment to lower cholesterol absorption efficiency and reduce the risk of these dietary cholesterol-induced diseases.